Alternative splicing and MicroRNA: epigenetic mystique in male reproduction

References

• Tournaye H, Krausz C, Oates RD. Novel concepts in the aetiology of male reproductive impairment. Lancet Diabetes Endocrinol. 2017;5(7):544–553.
   PubMed Web of Science ®Google Scholar
• Oatley JM, Brinster RL. Regulation of spermatogonial stem cell self-renewal in mammals. Annu Rev Cell Dev Biol. 2008;24:263–286.
   PubMed Web of Science ®Google Scholar
• Yan W. Male infertility caused by spermiogenic defects: lessons from gene knockouts. Mol Cell Endocrinol. 2009;306:24–32.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Shi J, Rassoulzadegan M, et al. Sperm RNA code programmes the metabolic health of offspring. Nat Rev Endocrinol. 2019;15:489–498.
   PubMed Web of Science ®Google Scholar
• Braunschweig U, Gueroussov S, Plocik AM, et al. Dynamic integration of splicing within gene regulatory pathways. Cell. 2013;152:1252–1269.
   PubMed Web of Science ®Google Scholar
• Merkin J, Russell C, Chen P, et al. Evolutionary dynamics of gene and isoform regulation in mammalian tissues. Science. 2012;338:1593–1599.
   PubMed Web of Science ®Google Scholar
• Qing G, Lu Q, Xiong Y, et al. New opportunities and challenges of smart polymers in post-translational modification proteomics. Adv Mater. 2017;29:20.
   Web of Science ®Google Scholar
• Nilsen TW, Graveley BR. Expansion of eukaryotic proteome by alternative splicing. Nature. 2010;463:457–463.
   PubMed Web of Science ®Google Scholar
• Scotti MM, Swanson MS. RNA-mis-splicing in disease. Nat Rev Genet. 2016;17:19–32.
   PubMed Web of Science ®Google Scholar
• Lee Y, Rio DC. Mechanisms and regulation of alternative pre-mRNA Splicing. Annu Rev Biochem. 2015;84:291–323.
   PubMed Web of Science ®Google Scholar
• Fica SM, Tuttle N, Novak T, et al. RNA catalyses nuclear pre-mRNA splicing. Nature. 2013;503:229–234.
   PubMed Web of Science ®Google Scholar
• Soumillon M, Necsulea A, Weier M, et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. Cell Rep. 2013;3:2179–2190.
   PubMed Web of Science ®Google Scholar
• Sharma U, Conine CC, Shea JM, et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science. 2016;351:391–396.
   PubMed Web of Science ®Google Scholar
• Filipowicz W, Bhattacharyya S, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008;9:102–114.
   PubMed Web of Science ®Google Scholar
• Conine CC, Sun F, Song L, et al. Small RNAs gained during epididymal transit of sperm are essential for embryonic development in mice. Dev Cell. 2018;46(470–480.e3):470–480.e3.
   PubMedGoogle Scholar
• Yuan S, Schuster A, Tang C, et al. Sperm-borne miRNAs and endo-siRNAs are important for fertilization and preimplantation embryonic development. Development. 2016;143:635–647.
   PubMed Web of Science ®Google Scholar
• Soubry A. Epigenetics as a driver of developmental origins of health and disease: did we forget the fathers? Bioessays. 2018;40:1.
   Web of Science ®Google Scholar
• Moholdt T, Hawley JA. Maternal Lifestyle Interventions: targeting Preconception Health. Trends Endocrinol Metab. 2020;S1043-2760(20):30058.
   Google Scholar
• Dupont C, Kappeler L, Saget S, et al. Role of miRNA in the transmission of metabolic diseases associated with paternal diet-induced obesity. Front Genet. 2019;10:337.
   PubMed Web of Science ®Google Scholar
• Rodgers AB, Morgan CP, Leu NA, et al. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc Natl Acad Sci U S A. 2015;112(44):13699–13704.
   PubMed Web of Science ®Google Scholar
• Tyebji S, Hannan AJ, Tonkin CJ. Pathogenic infection in male mice changes sperm small RNA profiles and transgenerationally alters offspring behavior. Cell Rep. 2020;31(4):107573.
   PubMed Web of Science ®Google Scholar
• Chan JC, Morgan CP, Adrian LN, et al. Reproductive tract extracellular vesicles are sufficient to transmit intergenerational stress and program neurodevelopment. Nat Commun. 2020;11:1499.
   PubMed Web of Science ®Google Scholar
• Manku G, Culty M. Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges. Reproduction. 2015;149:R139–157.
   PubMed Web of Science ®Google Scholar
• Gan H, Cai T, Lin X, et al. Integrative proteomic and transcriptomic analyses reveal multiple post-transcriptional regulatory mechanisms of mouse spermatogenesis. Mol Cell Proteomics. 2013;12:1144–1157.
   PubMed Web of Science ®Google Scholar
• Liao J, Suen HC, Luk ACS, et al. Transcriptomic and epigenomic profiling of young and aged spermatogonial stem cells reveals molecular targets regulating differentiation. PLoS Genet. 2021;17.
   Web of Science ®Google Scholar
• Liu W, Wang F, Xu Q, et al. BCAS2 is involved in alternative mRNA splicing in spermatogonia and the transition to meiosis. Nat Commun. 2017;8:14182.
   PubMed Web of Science ®Google Scholar
• Saeidi S, Shapouri F, de Iongh RU, et al. Esrp1 is a marker of mouse fetal germ cells and differentially expressed during spermatogenesis. PLoS ONE. 2018;13:e0190925.
   PubMed Web of Science ®Google Scholar
• Wang X, Lu Z, Gomez A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117–120.
   PubMed Web of Science ®Google Scholar
• Wang X, Zhao BS, Roundtree IA, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161:1388–1399.
   PubMed Web of Science ®Google Scholar
• Xiao W, Adhikari S, Dahal U, et.al. Nuclear m6A reader YTHDC1 regulates mRNA splicing. Mol Cell. 2016;61:507–519.
   PubMed Web of Science ®Google Scholar
• Liu J, Yue Y, Han D, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10:93–95.
   PubMed Web of Science ®Google Scholar
• Lin Z, Hsu PJ, Xing X, et al. Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis. Cell Res. 2017;27:1216–1230.
   PubMed Web of Science ®Google Scholar
• Xu K, Yang Y, Feng GH, et al. Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation. Cell Res. 2017;27:1100–1114.
   PubMed Web of Science ®Google Scholar
• Zhang L, Tang J, Haines CJ, et al. c-kit expression profile and regulatory factors during spermatogonial stem cell differentiation. BMC Dev Biol. 2013;13:38.
   PubMed Web of Science ®Google Scholar
• Rossi P, Marziali G, Albanesi C, et al. A novel c-Kit transcript, potentially encoding a truncated receptor, originates within a kit gene intron in mouse spermatids. Dev Biol. 1992;152:203–207.
   PubMed Web of Science ®Google Scholar
• Melino G, De Laurenzi V, Vousden KH. p73: friend or foe in tumorigenesis. Nat Rev Cancer. 2002;2:605–615.
   PubMed Web of Science ®Google Scholar
• Holembowski L, Kramer D, Riedel D, et al. TAp73 is essential for germ cell adhesion and maturation in testis. J Cell Biol. 2014;204:1173–1190.
   PubMed Web of Science ®Google Scholar
• Inoue S, Tomasini R, Rufini A, et al. TAp73 is required for spermatogenesis and the maintenance of male fertility. Proc Natl Acad Sci U S A. 2014;111:1843–1848.
   PubMed Web of Science ®Google Scholar
• Fu K, Tian S, Tan H, et al. Biological and RNA regulatory function of MOV10 in mammalian germ cells. BMC Biol. 2019;17:39.
   PubMed Web of Science ®Google Scholar
• Legrand JMD, Chan AL, La HM, et al. DDX5 plays essential transcriptional and post-transcriptional roles in the maintenance and function of spermatogonia. Nat Commun. 2019;10:2278.
   PubMed Web of Science ®Google Scholar
• Vourekas A, Zheng K, Fu Q, et al. The RNA helicase MOV10L1 binds piRNA precursors to initiate piRNA processing. Genes Dev. 2015;29:617–629.
   PubMed Web of Science ®Google Scholar
• Cheng CY, Mruk DD. Spermatogenesis, Mammals. In: Maloy S, Hughes K, editors. Brenner’s encyclopedia of genetics. 2nd ed. San Diego: Academic Press; 2013. p. 525–528.
   Google Scholar
• Schmid R, Grellscheid SN, Ehrmann I, et al. The splicing landscape is globally reprogrammed during male meiosis. Nucleic Acids Res. 2013;41:10170–10184.
   PubMed Web of Science ®Google Scholar
• Jenkins HT, Malkova B, Edwards TA. Kinked β-strands mediate high-affinity recognition of mRNA targets by the germ-cell regulator DAZL. Proc Natl Acad Sci U S A. 2011;108:18266–18271.
   PubMed Web of Science ®Google Scholar
• Reynolds N, Collier B, Bingham V, et al. Translation of the synaptonemal complex component Sycp3 is enhanced in vivo by the germ cell specific regulator Dazl. RNA. 2007;13:974–981.
   PubMed Web of Science ®Google Scholar
• Reynolds N, Collier B, Maratou K, et al. Dazl binds in vivo to specific transcripts and can regulate the pre-meiotic translation of Mvh in germ cells. Hum Mol Genet. 2005;14:3899–3909.
   PubMed Web of Science ®Google Scholar
• Kauppi L, Barchi M, Baudat F, et al. Distinct properties of the XY pseudoautosomal region crucial for male meiosis. Science. 2011;331(6019):916–920.
   PubMed Web of Science ®Google Scholar
• Carofiglio F, Inagaki A, de Vries S, et al. SPO11-independent DNA repair foci and their role in meiotic silencing. PLoS Genet. 2013;9(6):e1003538.
   PubMed Web of Science ®Google Scholar
• Cesari E, Loiarro M, Naro C, et al. Combinatorial control of Spo11 alternative splicing by modulation of RNA polymerase II dynamics and splicing factor recruitment during meiosis. Cell Death Dis. 2020;11:240.
   PubMed Web of Science ®Google Scholar
• Bao J, Tang C, Li J, et al. RNA-binding protein 9 is involved in alternative splicing and is critical for male germ cell development and male fertility. PLoS Genet. 2014;10:e1004825.
   PubMed Web of Science ®Google Scholar
• Puverel S, Barrick C, Dolci S, et al. RanBPM is essential for mouse spermatogenesis and oogenesis. Development. 2011;138:2511–2521.
   PubMed Web of Science ®Google Scholar
• Lemay JF, Lemieux C, St-André O, et al. Crossing the borders: poly(A)-binding proteins working on both sides of the fence. RNA Biol. 2011;7:291–295.
   Web of Science ®Google Scholar
• Yang J, Zhang Z, Zhang Y, et al. CLOCK interacts with RANBP9 and is involved in alternative splicing in spermatogenesis. Gene. 2018;642:199–204.
   PubMed Web of Science ®Google Scholar
• Paronetto MP, Messina V, Bianchi E, et al. Sam68 regulates translation of target mRNAs in male germ cells, necessary for mouse spermatogenesis. J Cell Biol. 2009;185:235–249.
   PubMed Web of Science ®Google Scholar
• Paronetto MP, Messina V, Barchi M, et al. Sam68 marks the transcriptionally active stages of spermatogenesis and modulates alternative splicing in male germ cells. Nucleic Acids Res. 2011;39:4961–4974.
   PubMed Web of Science ®Google Scholar
• Elliott DJ, Grellscheid SN. Alternative RNA splicing regulation in the testis. Reproduction. 2006;132:811–819.
   PubMed Web of Science ®Google Scholar
• Venables JP, Bourgeois CF, Dalgliesh C, et al. Up-regulation of the ubiquitous alternative splicing factor Tra2beta causes inclusion of a germ cell-specific exon. Hum Mol Genet. 2005;14:2289–2303.
   PubMed Web of Science ®Google Scholar
• Liu Y, Bourgeois CF, Pang S, et al. The germ cell nuclear proteins hnRNP G-T and RBMY activate a testis-specific exon. PLoS Genet. 2009;5:e1000707.
   PubMed Web of Science ®Google Scholar
• Dreumont N, Bourgeois CF, Lejeune F, et al. Human RBMY regulates germline-specific splicing events by modulating the function of the serine/arginine-rich proteins 9G8 and Tra2-beta. J Cell Sci. 2010;123:40–50.
   PubMed Web of Science ®Google Scholar
• Pedrotti S, Busà R, Compagnucci C, et al. The RNA recognition motif protein RBM11 is a novel tissue-specific splicing regulator. Nucleic Acids Res. 2012;40:1021–1032.
   PubMed Web of Science ®Google Scholar
• Di Giammartino DC, Nishida K, Manley JL. Mechanisms and consequences of alternative polyadenylation. Mol Cell. 2011;43:853–866.
   PubMed Web of Science ®Google Scholar
• Jia J, Yao P, Arif A, et al. Regulation and dysregulation of 3′ UTR-mediated translational control. Curr Opin Genet Dev. 2013;23:29–34.
   PubMed Web of Science ®Google Scholar
• MacDonald CC, McMahon KW. Tissue-specific mechanisms of alternative polyadenylation: testis, brain, and beyond. Wiley Interdiscip Rev RNA. 2010;1:494–501.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Tang C, Yu T, et al. MicroRNAs control mRNA fate by compartmentalization based on 3ʹ UTR length in male germ cells. Genome Biol. 2017;18:105.
   PubMed Web of Science ®Google Scholar
• Monteuuis G, Wong JJL, Bailey CG, et al. The changing paradigm of intron retention: regulation, ramifications and recipes. Nucleic Acids Res. 2019;47:11497–11513.
   PubMed Web of Science ®Google Scholar
• Wong JJ, Au AY, Ritchie W, et al. Intron retention in mRNA: no longer nonsense: known and putative roles of intron retention in normal and disease biology. Bioessays. 2016;38:41–49.
   PubMed Web of Science ®Google Scholar
• Naro C, Jolly A, Di Persio S, et al. An orchestrated intron retention program in meiosis controls timely usage of transcripts during germ cell differentiation. Dev Cell. 2017;41:82–93.
   PubMed Web of Science ®Google Scholar
• Izumikawa K, Yoshikawa H, Ishikawa H, et al. Chtop (Chromatin target of Prmt1) auto-regulates its expression level via intron retention and nonsense-mediated decay of its own mRNA. Nucleic Acids Res. 2016;44:9847–9859.
   PubMed Web of Science ®Google Scholar
• Ullrich S, Guigó R. Dynamic changes in intron retention are tightly associated with regulation of splicing factors and proliferative activity during B-cell development. Nucleic Acids Res. 2020;48:1327–1340.
   PubMed Web of Science ®Google Scholar
• Wong JJ, Ritchie W, Ebner OA, et al. Orchestrated intron retention regulates normal granulocyte differentiation. Cell. 2013;154:583–595.
   PubMed Web of Science ®Google Scholar
• Yao J, Ding D, Li X, et al. Prevalent intron retention fine-tunes gene expression and contributes to cellular senescence. Aging Cell. 2020;19:e13276.
   PubMed Web of Science ®Google Scholar
• Paronetto MP, Sette C. Role of RNA-binding proteins in mammalian spermatogenesis. Int J Androl. 2010;33:2–12.
   PubMedGoogle Scholar
• Gaucher J, Boussouar F, Montellier E, et al. Bromodomain-dependent stage-specific male genome programming by Brdt. EMBO J. 2012;31:3809–3820.
   PubMed Web of Science ®Google Scholar
• Berkovits BD, Wang L, Guarnieri P, et al. The testis-specific double bromodomain-containing protein BRDT forms a complex with multiple spliceosome components and is required for mRNA splicing and 3ʹ-UTR truncation in round spermatids. Nucleic Acids Res. 2012;40:7162–7175.
   PubMed Web of Science ®Google Scholar
• Manterola M, Brown TM, Oh MY, et al. BRDT is an essential epigenetic regulator for proper chromatin organization, silencing of sex chromosomes and crossover formation in male meiosis. PLoS Genet. 2018;14:e1007209.
   PubMed Web of Science ®Google Scholar
• Zheng G, Dahl JA, Niu Y, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49:18–29.
   PubMed Web of Science ®Google Scholar
• Tang C, Klukovich R, Peng H, et al. ALKBH5-dependent m6A demethylation controls splicing and stability of long 3′-UTR mRNAs in male germ cells. Proc Natl Acad Sci U S A. 2018;115:E325–E333.
   PubMed Web of Science ®Google Scholar
• Hsu PJ, Zhu Y, Ma H, et al. Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 2017;27:1115–1127.
   PubMed Web of Science ®Google Scholar
• Wojtas MN, Pandey RR, Mendel M, et al. Regulation of m6A transcripts by the 3ʹ→5ʹ RNA helicase YTHDC2 is essential for a successful meiotic program in the mammalian germline. Mol Cell. 2017;68:374–387.e12.
   PubMed Web of Science ®Google Scholar
• Abby E, Tourpin S, Ribeiro J, et al. Implementation of meiosis prophase I programme requires a conserved retinoid-independent stabilizer of meiotic transcripts. Nat Commun. 2016;7:10324.
   PubMed Web of Science ®Google Scholar
• Bailey AS, Batista PJ, Gold RS, et al. The conserved RNA helicase YTHDC2 regulates the transition from proliferation to differentiation in the germline. Elife. 2017;6:e26116.
   PubMed Web of Science ®Google Scholar
• Hannigan MM, Zagore LL, Licatalosi DD. Ptbp2 controls an alternative splicing network required for cell communication during spermatogenesis. Cell Rep. 2017;19:2598–2612.
   PubMed Web of Science ®Google Scholar
• Zagore LL, Grabinski SE, Sweet TJ, et al. RNA binding protein Ptbp2 is essential for male germ cell development. Mol Cell Biol. 2015;35:4030–4042.
   PubMed Web of Science ®Google Scholar
• Pivot-Pajot C, Caron C, Govin J, et al. Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein. Mol Cell Biol. 2003;23:5354–5365.
   PubMed Web of Science ®Google Scholar
• Rathke C, Baarends WM, Awe S, et al. Chromatin dynamics during spermiogenesis. Biochim Biophys Acta. 2014;1839:155–168.
   PubMed Web of Science ®Google Scholar
• Dhar S, Thota A, Rao MR. Insights into role of bromodomain, testis-specific (Brdt) in acetylated histone H4-dependent chromatin remodeling in mammalian spermiogenesis. J Biol Chem. 2012;287:6387–6405.
   PubMed Web of Science ®Google Scholar
• Morinière J, Rousseaux S, Steuerwald U, et al. Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature. 2009;461:664–668.
   PubMed Web of Science ®Google Scholar
• Luco RF, Pan Q, Tominaga K, et al. Regulation of alternative splicing by histone modifications. Science. 2010;327:996–1000.
   PubMed Web of Science ®Google Scholar
• Iwamori N, Tominaga K, Sato T, et al. MRG15 is required for pre-mRNA splicing and spermatogenesis. Proc Natl Acad Sci U S A. 2016;113:E5408–15.
   PubMed Web of Science ®Google Scholar
• O’Bryan MK, Clark BJ, McLaughlin EA, et al. RBM5 is a male germ cell splicing factor and is required for spermatid differentiation and male fertility. PLoS Genet. 2013;9:e1003628.
   PubMed Web of Science ®Google Scholar
• Bonnal S, Martinez C, Forch P, et al. RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition. Mol Cell. 2008;32:81–95.
   PubMed Web of Science ®Google Scholar
• Fushimi K, Ray P, Kar A, et al. Up-regulation of the proapoptotic caspase 2 splicing isoform by a candidate tumor suppressor, RBM5. Proc Natl Acad Sci U S A. 2008;105:15708–15713.
   PubMed Web of Science ®Google Scholar
• Mourão A, Bonnal S, Soni K, et al. Structural basis for the recognition of spliceosomal SmN/B/B’ proteins by the RBM5 OCRE domain in splicing regulation. Elife. 2016;5:e14707.
   PubMed Web of Science ®Google Scholar
• Baba T, Niida Y, Michikawa Y, et al. An acrosomal protein, sp32, in mammalian sperm is a binding protein specific for two proacrosins and an acrosin intermediate. J Biol Chem. 1994;269:10133–10140.
   PubMed Web of Science ®Google Scholar
• Kanemori Y, Ryu JH, Sudo M, et al. Two functional forms of ACRBP/sp32 are produced by premRNA alternative splicing in the mouse. Biol Reprod. 2013;88:105.
   PubMed Web of Science ®Google Scholar
• Kanemori Y, Koga Y, Sudo M, et al. Biogenesis of sperm acrosome is regulated by pre-mRNA alternative splicing of Acrbp in the mouse. Proc Natl Acad Sci U S A. 2016;113:E3696–3705.
   PubMed Web of Science ®Google Scholar
• Fang EF, Scheibye-Knudsen M, Chua KF, et al. Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol. 2016;17(5):308–321.
   PubMed Web of Science ®Google Scholar
• Tatone C, Di Emidio G, Barbonetti A, et al. Sirtuins in gamete biology and reproductive physiology: emerging roles and therapeutic potential in female and male infertility. Hum Reprod Update. 2018;24:267–289.
   PubMed Web of Science ®Google Scholar
• Michishita E, Park JY, Burneskis JM, et al. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell. 2005;16:4623–4635.
   PubMed Web of Science ®Google Scholar
• Bell EL, Nagamori I, Williams EO, et al. SirT1 is required in the male germ cell for differentiation and fecundity in mice. Development. 2014;141:3495–3504.
   PubMed Web of Science ®Google Scholar
• Di Sante G, Wang L, Wang C, et al. Sirt1-defificient mice have hypogonadotropic hypogonadism due to defective GnRH neuronal migration. Mol Endocrinol. 2015;29:200–212.
   PubMedGoogle Scholar
• Jiao D, Zhang H, Jiang Z, et al. MicroRNA-34a targets sirtuin 1 and leads to diabetes-induced testicular apoptotic cell death. J Mol Med. 2018;96:939–949.
   PubMed Web of Science ®Google Scholar
• Helmy HS, Senousy MA, El-Sahar AE, et al. Aberrations of miR-126-3p, miR-181a and Sirtuin1 Network Mediate Di-(2-ethylhexyl) phthalate-induced Testicular Damage in Rats: the Protective Role of Hesperidin. Toxicology. 2020;152406. 10.1016/j.tox.2020.152406
   PubMed Web of Science ®Google Scholar
• Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer. 2015;15:608–624.
   PubMed Web of Science ®Google Scholar
• Cheng A, Yang Y, Zhou Y, et al. Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell Metab. 2016;23:128–142.
   PubMed Web of Science ®Google Scholar
• North BJ, Rosenberg MA, Jeganathan KB, et al. SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J. 2014;33:1438–1453.
   PubMed Web of Science ®Google Scholar
• Kanfi Y, Naiman S, Amir G, et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012;483:218–221.
   PubMed Web of Science ®Google Scholar
• Mostoslavsky R, Chua KF, Lombard DB, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006;124:315–329.
   PubMed Web of Science ®Google Scholar
• Ryu D, Jo YS, Lo Sasso G, et al. A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function. Cell Metab. 2014;20:856–869.
   PubMed Web of Science ®Google Scholar
• Dai X, Yan X, Wintergerst KA, et al. Nrf2: redox and metabolic regulator of stem cell state and function. Trends Mol Med. 2020;26:185–200.
   PubMed Web of Science ®Google Scholar
• Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014;39:199–218.
   PubMed Web of Science ®Google Scholar
• Silva-Palacios A, Ostolga-Chavarría M, Zazueta C, et al. Nrf2: molecular and epigenetic regulation during aging. Ageing Res Rev. 2018;47:31–40.
   PubMed Web of Science ®Google Scholar
• Wang H, Liu K, Geng M, et al. RXRα inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res. 2013;73:3097–3108.
   PubMed Web of Science ®Google Scholar
• Moldogazieva NT, Lutsenko SV, Terentiev AA. Reactive oxygen and nitrogen species-induced protein modifications: implication in carcinogenesis and anticancer therapy. Cancer Res. 2018;78(21):6040–6047.
   PubMed Web of Science ®Google Scholar
• Azzimato V, Jager J, Chen P, et al. Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance. Sci Transl Med. 2020;12:eaaw9709.
   PubMed Web of Science ®Google Scholar
• Qin Z, Zhu K, Xue J, et al. Zinc-induced protective effect for testicular ischemia-reperfusion injury by promoting antioxidation via microRNA-101-3p/Nrf2 pathway. Aging (Albany NY). 2019;11:9295–9309.
   PubMedGoogle Scholar
• Zhao XJ, Yu HW, Yang YZ, et al., Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway. Redox Biol Redox Biol. 2018; 18:124–137.
   PubMed Web of Science ®Google Scholar
• Poganik JR, Long MJC, Disare MT, et al. Post-transcriptional regulation of Nrf2-mRNA by the mRNA-binding proteins HuR and AUF1. FASEB J. 2019;33:14636–14652.
   PubMed Web of Science ®Google Scholar
• Sánchez-Martín P, Komatsu M. p62/SQSTM1-steering the cell through health and disease. J Cell Sci. 2018;131(21):jcs222836.
   PubMed Web of Science ®Google Scholar
• Yang C, Yao C, Tian R, et al. miR-202-3p regulates sertoli cell proliferation, synthesis function, and apoptosis by targeting LRP6 and cyclin D1 of Wnt/β-catenin signaling. Mol Ther Nucleic Acids. 2019;14:1–19.
   PubMedGoogle Scholar
• Leung L, Kwong M, Hou S, et al. Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress. J Biol Chem. 2003;278(48):48021–48029.
   PubMed Web of Science ®Google Scholar
• Wakabayashi N, Itoh K, Wakabayashi J, et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet. 2003;35:238–245.
   PubMed Web of Science ®Google Scholar
• Nakamura BN, Lawson G, Chan JY, et al. Knockout of the transcription factor NRF2 disrupts spermatogenesis in an age-dependent manner. Free Radic Biol Med. 2010;49:1368–1379.
   PubMed Web of Science ®Google Scholar
• Chen K, Mai Z, Zhou Y, et al. Low NRF2 mRNA expression in spermatozoa from men with low sperm motility. Tohoku J Exp Med. 2012;228(3):259–266.
   PubMed Web of Science ®Google Scholar
• Yu B, Lin H, Yang L, et al. Genetic variation in the Nrf2 promoter associates with defective spermatogenesis in humans. J Mol Med (Berl). 2012;90:1333–1342.
   PubMed Web of Science ®Google Scholar
• López P, Castro A, Flórez M, et al. miR-155 and miR-122 Expression of Spermatozoa in Obese Subjects. Front Genet. 2018;9:175.
   PubMed Web of Science ®Google Scholar
• Yehuda R, Lehrner A. Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms. World Psychiatry. 2018;17:243–257.
   PubMed Web of Science ®Google Scholar
• Fullston T, Ohlsson-Teague EM, Print CG, et al. Sperm microRNA content is altered in a mouse model of male obesity, but the same suite of micrornas are not altered in offspring’s sperm. PLoS One. 2016;11:e0166076.
   PubMed Web of Science ®Google Scholar
• Cropley JE, Eaton SA, Aiken A, et al. Male-lineage transmission of an acquired metabolic phenotype induced by grand-paternal obesity. Mol Metab. 2016;5:699–708.
   PubMed Web of Science ®Google Scholar
• de Castro Barbosa T, Ingerslev LR, Alm PS, et al. High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring. Mol Metab. 2015;5:184–197.
   PubMed Web of Science ®Google Scholar
• Grandjean V, Fourré S, De Abreu DA, et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci Rep. 2015;5:18193.
   PubMed Web of Science ®Google Scholar
• Murashov AK, Pak ES, Koury M; Murashov AK, Pak ES, Koury M, Ajmera A, Jeyakumar M, Williams O, Ding J, Walters D, Neufer PD. Paternal long-term exercise programs offspring for low energy expenditure and increased risk for obesity in mice. FASEB J. 2016;30:775–784.
   PubMed Web of Science ®Google Scholar
• Carone BR, Fauquier L, Habib N, et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010;143:1084–1096.
   PubMed Web of Science ®Google Scholar
• Dickson DA, Paulus JK, Mensah V, et al. Reduced levels of miRNAs 449 and 34 in sperm of mice and men exposed to early life stress. Transl Psychiatry. 2018;8:101.
   PubMed Web of Science ®Google Scholar
• Cheeseman K, Weitzman JB. Host-parasite interactions: an intimate epigenetic relationship. Cell Microbiol. 2015;17(8):1121–1132.
   PubMed Web of Science ®Google Scholar
• Pellati D, Mylonakis I, Bertoloni G, et al. Genital tract infections and infertility. Eur J Obstet Gynecol Reprod Biol. 2008;140:3–11.
   PubMed Web of Science ®Google Scholar
• Knuesel I, Chicha L, Britschgi M, et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. 2014;10:643–660.
   PubMed Web of Science ®Google Scholar
• Melamed Z, Levy A, Ashwal-Fluss R, et al. Alternative splicing regulates biogenesis of miRNAs located across exon-intron junctions. Mol Cell. 2013;50:869–881.
   PubMed Web of Science ®Google Scholar
• Levine DC, Hong H, Weidemann BJ, et al. NAD controls circadian reprogramming through PER2 nuclear translocation to counter aging. Mol Cell. 2020;78:835–849.
   PubMed Web of Science ®Google Scholar
• Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14:612–622.
   PubMed Web of Science ®Google Scholar
• Saito Y, Yako T, Otsu W, et al. A triterpenoid Nrf2 activator, RS9, promotes LC3-associated phagocytosis of photoreceptor outer segments in a p62-independent manner. Free Radic Biol Med. 2020;152:235–247.
   PubMed Web of Science ®Google Scholar
• Panneerdoss S, Viswanadhapalli S, Abdelfattah N, et al. Cross-talk between miR-471-5p and autophagy component proteins regulates LC3-associated phagocytosis (LAP) of apoptotic germ cells. Nat Commun. 2017;8:598.
   PubMed Web of Science ®Google Scholar
• Chen Q, Yan M, Cao Z, et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science. 2016;351(6271):397–400.
   PubMed Web of Science ®Google Scholar
• Kazachenka A, Bertozzi TM, Sjoberg-Herrera MK, et al. Identification, characterization, and heritability of murine metastable epialleles: implications for non-genetic inheritance. Cell. 2018;175(5):1259–1271.e13.
   PubMed Web of Science ®Google Scholar
• Kiani J, Grandjean V, Liebers R, et al. RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dnmt2. PLoS Genet. 2013;9(5):e1003498.
   PubMed Web of Science ®Google Scholar
• Ding N, Zhang X, Zhang XD, et al. Impairment of spermatogenesis and sperm motility by the high-fat diet-induced dysbiosis of gut microbes. Gut. 2020;gutjnl-2019-319127.
   Web of Science ®Google Scholar
• Qi X, Yun C, Sun L, et al. Gut microbiota-bile acidinterleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med. 2019;25:1225–1233.
   PubMed Web of Science ®Google Scholar
• Wang X, Li Y, Chen W, et al. Transcriptome-wide reprogramming of N6-methyladenosine modification by the mouse microbiome. Cell Res. 2019;29:167–170.
   PubMed Web of Science ®Google Scholar
• Skvortsova K, Iovino N, Bogdanovic O. Functions and mechanisms of epigenetic inheritance in animals. Nat Rev Mol Cell Biol. 2018;19:774–790.
   PubMed Web of Science ®Google Scholar
• Gao H, Wen H, Cao C, et al. Overexpression of MicroRNA-10a in germ cells causes male infertility by targeting Rad51 in mouse and human. Front Physiol. 2019;10:765.
   PubMed Web of Science ®Google Scholar
• Li L, Zhu Y, Chen T, et al. MiR-125b-2 knockout in testis is associated with targeting to the PAP gene, mitochondrial copy number, and impaired sperm quality. Int J Mol Sci. 2019;20:148.
   PubMed Web of Science ®Google Scholar
• Chen J, Cai T, Zheng C, et al. MicroRNA-202 maintains spermatogonial stem cells by inhibiting cell cycle regulators and RNA binding proteins. Nucleic Acids Res. 2017;45:4142–4157.
   PubMed Web of Science ®Google Scholar
• Cui N, Hao G, Zhao Z, et al. MicroRNA-224 regulates self-renewal of mouse spermatogonial stem cellsviatargeting DMRT1. J Cell Mol Med. 2016;20(8):1503–1512.
   PubMed Web of Science ®Google Scholar
• Bao J, Li D, Wang L, et al. MicroRNA-449 and MicroRNA-34b/c function redundantly in murine testes by targeting E2F transcription factor-retinoblastoma Protein (E2F-pRb) pathway. J Biol Chem. 2012;287:21686–21698.
   PubMed Web of Science ®Google Scholar
• Comazzetto S, Di Giacomo M, Rasmussen KD, et al. Oligoasthenoteratozoospermia and infertility in mice deficient for miR-34b/c and miR-449 Loci. PLoS Genet. 2014;10:e1004597.
   PubMed Web of Science ®Google Scholar
• Moritoki Y, Hayashi Y, Mizuno K, et al. Expression profiling of microRNA in cryptorchid testes: miR-135a contributes to the maintenance of spermatogonial stem cells by regulating FoxO1. J Urol. 2014;191:1174–1180.
   PubMed Web of Science ®Google Scholar
• Yang QE, Racicot KE, Kaucher AV, et al. MicroRNAs 221 and 222 regulate the undifferentiated state in mammalian male germ cells. Development. 2012;140(2):280–290.
   PubMed Web of Science ®Google Scholar
• Dai L, Tsai-Morris CH, Sato H, et al. Testis-specific miRNA-469 up-regulated in gonadotropin-regulated testicular RNA helicase (GRTH/DDX25)-null mice silences transition protein 2 and protamine 2 messages at sites within coding region. J Biol Chem. 2011;286:44306–44318.
   PubMed Web of Science ®Google Scholar
• Niu Z, Goodyear SM, Rao S, et al. MicroRNA-21 regulates the self-renewal of mouse spermatogonial stem cells. Proc Nat Acad Sci. 2011;108:12740–12745.
   PubMed Web of Science ®Google Scholar
• Ramaiah M, Tan K, Plank TM, et al. A microRNA cluster in the Fragile-X region expressed during spermatogenesis targets FMR1. EMBO Rep. 2019;20(2):e46566.
   PubMed Web of Science ®Google Scholar
• Yang Y, Willis TL, Button RW, et al. Cytoplasmic DAXX drives SQSTM1/p62 phase condensation to activate Nrf2-mediated stress response. Nat Commun. 2019;10:3759.
   PubMed Web of Science ®Google Scholar
• Zhang L, Ma J, Yang B, et al. Interference with lactate metabolism by mmu-miR-320-3p via negatively regulating GLUT3 signaling in mouse Sertoli cells. Cell Death Dis. 2018;9:10.
   PubMed Web of Science ®Google Scholar
• Xu Y, Wu W, Fan Y, et al. MiR-142-3p inhibits TGF-β3-induced blood-testis barrier impairment by targeting lethal giant larvae homolog 2. Cell Physiol Biochem. 2018;46(1):253–268.
   PubMedGoogle Scholar
• Nakagawa T, Nabeshima Y, Yoshida S. Functional Identification of the actual and potential stem cell compartments in mouse spermatogenesis. Dev Cell. 2007;12:195–206.
   PubMed Web of Science ®Google Scholar